Oxidants are normal by-products of cell metabolism. However, reactive oxygen species such as superoxide (“O2−”) and reactive intermediates formed from O2− are known to damage biological targets. For example, J. Lee et al., J. Am. Chem. Soc. 120:7493-7501 (1998) discloses that reactive oxygen and nitrogen species play a role in the regulation and inhibition of mitochondrial respiration and apoptosis.
S. Cuzzocrea et al., Pharm. Rev., 53:135-159 (2001) discloses that biologically relevant free-radicals derived from oxygen include O2−, perhydroxyl radical (“HO2−”), and nitric oxide (“NO”). One source of O2− is a proinflammatory cytokine, which produces O2− during reperfusion following ischemia. This reference discloses that reaction of NO with O2− forms the reactive peroxynitrite ion (“ONOO−”) according to the reaction:NO+O2−→ONOO−The reference further discloses that formation of ONOO— enhances the cytotoxic potential of NO and O2−.
In animals, a superoxide dismutase (“SOD”) counters the effects of these reactive species. SODs are metalloenzymes that catalyze the conversion of O2− to hydrogen peroxide and oxygen according to the reaction:2 O2−+2 H+→H2O2+O2
It is reported that certain synthetic metallomacrocyles also catalyze the transformation of reactive species into less reactive products. U.S. Pat. No. 6,204,259 to Riley et al. discloses that a pentazamacrocycle comprising a Mn(II) or Mn(III) metal can catalyze the conversion of O2− into oxygen and hydrogen peroxide.
Spasojevic et al., Biology and Chemistry 4(5):526-533 (2000) discloses that tetrakis-5,10,15,20-(2-N-ethylpyridinium)porphyrinato complexes of manganese(II) and manganese(III) are catalytic scavengers of oxygen.
J. Lee et al., J. Am. Chem. Soc. 120:7493-7501 (1998) discloses that O2− and ONOO− are decomposed by the metalloporphyrin 5,10,15,20-tetrakis(N-methyl-4-pyridyl)porphinatoiron(III).
Lee et al., Bioorg. Med. Chem. Letters 7:2913-2918 (1997) discloses that 5,10,15,20-tetrakis(N-methyl-4-pyridinium)porphinatomanganese(III) catalyzes the reduction of ONOO− in the presence of biological antioxidants such as vitamin C, gluthionate, and vitamin E.
U.S. Pat. No. 5,630,137 to Nguyen et al. discloses a cosmetic composition containing SODs in combination with metalloporphyrins that is allegedly useful to treat skin and hair disorders caused by free radicals. This patent discloses the use of naturally occurring metalloporphyrins such as chlorophyll, chlorophyllin and hemoglobin to allegedly reinforce the anti-free radical action of the SOD.
German Patent Publication No. DE 19647640 A1 discloses a metalloporphyrin dimer in which two metalloporphyrin compounds are covalently joined at the meso position of the porphyrin rings. The patent publication alleges that the dimer is useful for catalyzing oxygen-transfer processes.
International Publication No. WO 99/55388 discloses meso-substituted metalloporphyrin complexes in which the meso substituents are ester, alkyl, alkyl halide, and amide groups. This publication further alleges that such compounds are useful for modulating the cellular levels of oxidants and the processes in which these oxidants participate.
Metalloporphyrins are also reported to inhibit telomerase activity by binding to quadraplex DNA. For example, Shi et al., J. Med. Chem. 44:4509-4523 (2002) discloses that cationic forms of meso-tetrakis(N-methylpyridinium)metalloporphyrins interact with the quadraplex structure of DNA.
U.S. Pat. No. 6,087,493 to Wheelhouse et al. discloses meso-tetrakis(pyridyl)metalloporphyrins in which the nitrogen atom of the pyridyl rings are substituted with hydrogen, alkyl, alkylhydroxy, alkylamine, alkylacetate or alkylsulfate groups. This patent alleges that such compounds are useful as telomerase inhibitors.
U.S. Pat. No. 6,204,259 to Riley et al. discloses that pentazamacrocycles comprising a Mn(II) or Mn(III) metal are allegedly useful for treating inflammatory disease states and reperfusion injury.
U.S. Pat. No. 6,127,356 to Crapo et al. discloses meso-substituted metalloporphyrins in which the meso substituents are aryl, substituted aryl, cycloalkyl, 4-pyridyl or N-substituted 4-pyridyl groups. This patent further discloses meso-tetrakis(pyridinium)metalloporphyrins in which the nitrogen atom of the pyridyl ring is substituted with an alkyl group, alkylhydroxy, alkylamine, alkylcarboxylate, alkysulfate or alkylphospate. The patent alleges that the disclosed metalloporphyrins act as mimetics of SODs.
Misko et al., J. Biol. Chem. 273:15646-15653 (1998) discloses that 5,10,15,20-tetrakis(N-methyl-4-pyridinium)porphinatoiron(III) catalyzes the conversion of ONOO− into nitrate. The authors also disclose that 5,10,15,20-tetrakis(N-methyl-4-pyridinium) porphinatoiron(III) is allegedly useful for reducing cellular damage at sites of inflammation.
International Publication No. WO 00/75144 A2 discloses 5,10,15,20-tetrakis(N-alkylpyridinum)metalloporphyrins in which the pyridyl fragments are joined to the meso carbon atoms of the porphyrin ring at the 2(“ortho”), 3(“meta”) or 4(“para”) position of the pyridyl ring relative to the nitrogen atom. The publication alleges that the meso-tetrakis(N-alkylpyridinium)metalloporphyrins are useful for treating inflammation diseases including arthritis, inflammatory bowel disease and acute respiratory disease syndrome, and for the treatment of ischemia-reperfusion injury.
U.S. Pat. No. 5,994,339 to Crapo et al. discloses Mn—, Fe— and Cu-based 5,10,15,20-tetrakis(N-alkyl-4-pyridinium)metalloporphyrins in which the nitrogen atom of the pyridyl ring is substituted with an alkyl, alkylhydroxy, alkylamine, alkylcarboxylate, alkylsulfate or alkyphosphate group. This patent also alleges that 5,10,15,20-tetrakis(N-alkyl-4-pyridinium)metalloporphyrins are useful as mimetics of SODs and for the treatment of an inflammatory condition.
U.S. Pat. No. 6,245,758 B1 to Stern et al. discloses the use of 5,10,15,20-tetrakis(pyridyl)metalloporphyrins, and their corresponding N-alkylpyridinium salts, to allegedly treat disorders including inflammation disease and ischemic reperfusion. Metals allegedly useful in the metalloporphyrins include Mn, Fe, Ni and V.
U.S. patent application Publication 2002/0042407 to Fridovich et al. discloses that 5,10,15,20-tetrakis(N-alkylpyridinium)metalloporphyrins are allegedly useful for modulating the intra-or extracellular levels of oxidants such as O2−. Metals allegedly useful in the metalloporphyrins include Fe, Mn, Co, Ni and Zn. The publication also discloses methods for using these 5,10,15,20-tetrakis(N-alkylpyridinium)metalloporphyrins to allegedly treat disorders such as inflammatory diseases of the skin and lungs, ischemia reperfusion injury; eye disorders such as glaucoma, macular degeneration and cataracts; and diseases of the central nervous system.
There remains, however, a clear need for compounds, compositions and methods for that are useful for treating or preventing injury due to exposure to a reactive species, erectile dysfunction due to surgery, lung disease, hyperoxia, neurodegenerative disease, liver disease, myocardial damage during cardioplegia, an inflammatory condition, a reperfusion injury, an ischemic condition, a cardiovascular disease, diabetes, a diabetic complication, cancer, a side-effect of cancer chemotherapy, or a radiation-induced injury, or to prolong the half-life of an oxidation-prone compound.
Citation of any reference in Section 2 of this application is not an admission that the reference is prior art to this application.